Intracerebral hemorrhage (ICH) has the highest morbidity, disability, and mortality rates of any stroke subtype, including ischemic stroke. When a hemorrhagic stroke occurs, the blood-brain barrier is broken and blood components enter the brain. A major cause of morbidity and mortality following brain hemorrhage is the direct toxicity of the blood components, mainly free hemoglobin (Hb), on adjacent brain tissue. The acute phase plasma protein haptoglobin (Hp) binds to Hb and inhibits its cytotoxic, pro-oxidative, and pro-inflammatory properties. Normally, the Hp-Hb complexes are cleared by CD163, a receptor present on macrophages, monocytes, and microglia. A soluble form of this receptor (sCD163) exists, and has recently been shown to bind Hp-Hb complexes with high affinity and participate in Hb clearance by two separate pathways. Therefore, locally upregulating the Hp-CD163 system has the potential to increase the clearance of Hb from the brain, and could represent an important clinically relevant strategy for the treatment of hemorrhagic stroke. Accordingly, we plan to test two ways to induce Hp expression in the brain: 1) using a natural compound pathway (based on preliminary data), and 2) using the adeno-associated virus (AAV) vector. Similarly, we will also use the AAV vector to upregulate expression of sCD163. Our working hypothesis is that Hp and/or CD163 are neuroprotective following brain hemorrhage in two ways: 1) by sequestering extracellular pro-oxidant Hb and 2) by mediating its safe degradation via CD163. This hypothesis will be tested in the specific aims listed below using wildtype, Hp knockout, and CD163 knockout C57BL/6 mice. Aim 1: To investigate the role of haptoglobin and CD163 on anatomical and functional outcomes following intracerebral hemorrhage. Aim 2: To determine whether upregulating haptoglobin and/or CD163 expression is beneficial after intracerebral hemorrhage. A better understanding of how toxic free Hb is managed and cleared from the central nervous system following brain hemorrhage is crucial for both understanding the pathophysiology of the heme-related secondary complications following ICH, but also for the subsequent design of more effective treatments in the future. It is of particular importance for ICH because it is an acute debilitating neurological disorder that has no effective treatments, though we are confident that the knowledge gained here will also be applicable to other conditions in which blood is released within the brain.